Design and synthesis of quinolinopropellane derivatives with selective δ opioid receptor agonism |
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| Institution: | 1. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan;2. Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan;3. Laboratory of Physical Chemistry for Drug Design, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan;4. Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan;5. School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan;1. Drug Design and Synthesis Section, Molecular Targets and Medications Discovery Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA;2. Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Department of Health and Human Services, 9800 Medical Center Drive, Bethesda, MD 20892-3373, USA;3. Medicinal Chemistry Section, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA;1. Department of Drug Sciences-Medicinal Chemistry Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy;2. Department of Drug Sciences-Pharmacology and Toxicology Section, University of Catania, Viale A. Doria 6, 95125 Catania, Italy;1. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan;2. Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan;3. Pharmaceutical Research Laboratories, Toray Industries Inc., 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan;4. R&D Center for Frontiers of Mirai in Policy and Technology (F-MIRAI), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan;5. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;1. Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan;2. International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8575, Japan;3. School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan;4. Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, Tokyo 187-8553, Japan |
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| Abstract: | Indolopropellane 2 was reported to show almost no binding affinity to the δ opioid receptor (DOR) in spite of the fact that 2 has both the propellane fundamental skeleton (message part) with binding ability to the opioid receptors and a possible DOR address structure (indole moiety). We developed the working hypothesis that almost no binding affinity of 2 to the DOR would be derived from its possibly stable bent conformer. To enable the propellane skeleton to adopt an extended conformation which would reasonably interact with the DOR, quinolinopropellanes 3a–d were designed which had an additional pharmacophore, quinoline nitrogen. The calculated binding free energies of ligand–DOR complexes strongly supported our working hypothesis. The synthesized quinolinopropellane 3a was a selective DOR full agonist, confirming our working hypothesis and the results of in silico investigation. |
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| Keywords: | Opioid DOR Propellane structure Binding mode Binding free energy |
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